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No WAVE, no reward: hope for addictive brains

Cocaine is a common illicit drug of abuse which is able to strongly modify the brain. Cocaine-induced synaptic modifications are implicated in the neuronal adaptations underling addiction. Cocaine is able to increase the synaptic contents of dopamine (the “feel-good” chemical), by blocking the dopamine transporter (DAT) which is in charge for the synaptic re-uptake of the neurotransmitter. This massive increase in dopamine produces euphoria and pleasure. Despite several decades of efforts, the cellular and molecular mechanisms responsible for cocaine-induced neuronal maladaptations are far from being completely understood and unveiled.

In a recent PNAS article, the laboratory of Paul Greengard (Nobel Prize in Medicine in 2000) has revealed for the first time how a protein called WAVE1 is able to regulate the brain’s response to cocaine. Indeed, these results provide novel insights into the molecular functioning of the “addicted brain” and could lead to better interventions for treating addiction to cocaine and other drugs.

“We knew about the connection between WAVE1 and dopamine many years ago, but until now no one knew the mechanisms by which cocaine stimulates WAVE1 and how WAVE1 regulates cocaine’s actions” says Yong Kim, a Research Assistant Professor in Greengard’s lab and the senior author of the new study.

In particular, the authors showed that WAVE1 was necessary to induce the rewarding and psychomotor effects of cocaine administration by knocking-down WAVE1 in the dopaminoceptive neurons of the nucleus accumbens (NAc), a brain region highly involved in reward and motivation. However, it must be noted that the neurons of the NAc are not all the same. In fact, the nucleus accumbens is mainly composed of medium-sized spiny neurons (MSNs) which can be further subdivided depending on the expression of the dopamine receptor 1 (D1R) or the dopamine receptor 2 (D2R). We can then distinguish D1R-MSNs and D2R-MSNs. Surprisingly, cocaine-induced behavioral alterations were strongly reduced only when WAVE1 was genetically ablated in D1R-MSNs. However, this effect was not observed when WAVE1 was removed from cells containing the D2R, thus revealing new details about the neurobiological mechanisms of cocaine. In addition, the authors observed that WAVE1 phosphorylation was modulated by dopamine through its dopamine D1R receptor since pharmacological blockade of this specific receptor was able to block cocaine-induced WAVE1 post-translational modifications.

Interestingly, this study also provides new evidence regarding the functional role of WAVE1 at the level of the brain’s synapses, the tiny junctions between neuronal cells through which impulses pass. The authors observed that WAVE1 activation is associated with morphological and functional decreases in excitatory synapses on specific D1R-MSNs. Importantly, “certain polymorphisms in WAVE1 complex proteins in humans might contribute to vulnerability in functional plasticity of glutamatergic synapses underlying addiction behavior such as cocaine craving and relapse”, say Ilaria Ceglia, the leading author of the study. Altogether the results suggest that this protein may play a critical role in providing a regulatory negative feedback at the level of specific excitatory synapses as a part of the cellular and molecular maladaptations induced by cocaine.

“It’s well known that cocaine increases the signaling of dopamine in the brain” Kim says. “Understanding more about the mechanism of cocaine action is providing new insights into the neurobiology of addiction. Our eventual goal is to use these findings to find a way to develop a drug to treat addiction”, conclude the authors.

Further studies will obviously be required to deeply understand all the molecular actors responsible for the psychostimulant effects induced by cocaine.

Any views expressed are those of the author, and do not necessarily reflect those of PLOS.

Giuseppe Gangarossa received his PhD in Biomedical Sciences, specialty Neuroscience, from the University of Bologna. He has been a visiting fellow at the Karolinska Institutet (Sotckholm, Sweden), the French Inserm (Montpellier, France) and the Collège de France (Paris, France). Giuseppe is currently Assistant Professor of Physiology at the University Paris Diderot. His main research topic is dopamine-related brain disorders. You can follow him on twitter @PeppeGanga

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